(671b) Reaction Development for Bench Scale, Continuous Synthesis of a Drug Substance

Recently the pharmaceutical industry has shown an increased interest in implementing continuous manufacturing processes. While this movement has been supported by the Food and Drug Administration, there have been limited reports of continuous production systems. We have worked within the Novartis-MIT Center for Continuous Manufacturing to develop a fully integrated, bench scale process for taking chemical intermediates to a coated tablet. This talk will highlight the reaction development and operation for the two chemical transformations performed. Translating unit operations from batch to continuous required the development of different reaction conditions. Reaction times were significantly decreased and solvent usage was reduced or even eliminated. The increased heat transfer available to continuous processes was utilized to perform a rapid, exothermic quench not possible in batch operation.

Operating a continuous synthesis process at the bench scale required addressing several issues not present in smaller, isolated systems. A thorough understanding of mixing was important for operation at the bench scale where neither the short diffusion times of microreactors nor the turbulent flow of pilot plants were present. This was addressed in multiple ways including modeling the residence time distribution and making use of in situ gas formation to promote mixing. Monitoring of chemical composition was required to maintain reaction stoichiometry and was achieved using a variety of online measurements including UV and IR spectroscopy and density. Lastly, the bench scale system provided a challenging scale up for membrane based liquid-liquid separators originally developed for microscale continuous multistep synthesis (1).

References:

1. H. R. Sahoo, J. G. Kralj, K. F. Jensen, Angew. Chem. Int. Ed. 2007, 46, 5704.